Although a staggering array of drugs is available for disorders such as cancer and autoimmunity, much remains unknown about their genetic targets. Researchers currently depend upon cumbersome and expensive screens to develop drugs specific for therapeutic candidate genes. Further, pharmacological and computational studies suggest many widely-used drugs exert their desired effects through off-target interactions. This research proposes a general, low-cost platform to identify specific genetic targets for drugs and to better understand the relevant biological pathways. The project repurposes the technology of radiation hybrid (RH) panels, a resource that was invented nearly 40 years ago for high resolution genetic mapping of the mammalian genome. RH cells contain extra copies of randomly selected genes and offer the opportunity to pinpoint functional drug/gene interactions with high precision. Our results will provide a powerful technology to speed and refine the connections between pharmacology and genetics. We will study a long-standing RH panel which we have genetically characterized using modern genotyping technologies. (We have used the panel to identify a gene in the Wnt signaling pathway as dominant in the action of the anti-microtubule drugs paclitaxel and colchicine.) We will also incorporate the bulk segregant approach to create large pools of RH cells, which will enable us to examine the genomes of thousands of cells. This work will offer an unprecedented view of the genetics of drug action and also offers a low-cost and effective platform for genome-wide experiments in mammalian pharmacology, physiology and cell biology.